Abstract The immune system is a complex but highly plastic biological defense system that normally protects the host against infection and damage. However, in some disease states, such as cancer, the usually well-orchestrated immune response fails to protect the host and instead exacerbates disease. Because the immune system is highly plastic, however, novel therapeutics may be able to restore normal immune responses that combat cancer. There is a critical need to develop novel therapies for oral cancers, such as head and neck squamous cell carcinoma (HNSCC), a deadly and disfiguring disease that accounts for an estimated 59,340 cases (43,390 men and 15,950 women) and 12,290 deaths each year in the United States. The incidence of HNSCC is rapidly rising in the United States and worldwide, in part due to increases in human papillomavirus (HPV) associated oropharynx cancers. While current immune therapies hold new promise for the treatment of cancer, the checkpoint inhibitor nivolumab (anti-PD-1) recently demonstrated only modest single agent activity in recurrent/metastatic HNSCC, as one-year survival and response rates were only 36% and 13%, respectively, in a Phase 3 trial. Improved therapeutic approaches that target additional mechanisms of immune escape in combination with checkpoint inhibitors could hold promise for this disease. Our recent studies (Nature 2016) showed that immune suppressive Tumor Associated Macrophages (TAMs) promote HNSCC immune escape. We found that two macrophage proteins, phosphatidylinositol-4,5-bisphosphate 3-kinase gamma PI3K? inhibition repolarized macrophages and synergized with anti-PD-1 to enhance recruitment and activation of IFN?+ cytotoxic CD8+ T cells. These results indicate that therapeutic strategies that target TAMs as well as T cell checkpoints could improve HNSCC patient outcomes. We propose to test the overall hypothesis that therapeutic strategies that block macrophage-mediated immune suppression will synergize with T cell targeted therapeutics to improve outcomes in HNSCC disease. The specific aims of this proposal are: 1) To determine how immune suppressive myeloid cells are recruited to HNSCC tumors. 2) To identify how myeloid cell polarization is controlled during HNSCC tumor progression. 3) To identify novel immune therapeutic strategies and immune biomarkers for HNSCC disease.